The rationale for this proposal rests on the hypothesis that in some instances HLA polymorphisms confer risk for autoimmunity by means of their influence on the thymic selection events which shape the mature T cell repertoire. This proposal will explore one aspect of this problem in depth, namely the variation and genetic regulation of J segment frequency and CDR3 length in peripheral T cells. Preliminary data indicate that these parameters exhibit substantial variation between individuals. The experimental approach will particularly focus on HLA alleles which have been implicated in rheumatoid arthritis, although the primary goal of these studies is to investigate the normal T cell repertoire and define genetic factors which regulate it. Specific aim 1: We will determine the normal range of variation in J segment frequency and CDR3 length within each T cell receptor Vbeta family. Specific aim 2: We will test the hypothesis that variation in these parameters (J segment frequency and CDR3 length) of the T cell repertoire is under genetic control, and not simply a result of antigenic exposure. We will therefore compare these parameters in normal monozygotic (MZ) twin pairs, as well as dizygotic (DZ) twins and sibling pairs. In addition, we will also examine the T cell repertoire of human cord blood T cells, on the assumption that these cells are reflective of the "naive" T cell repertoire. Specific aim 3: If, as expected, specific aims 1 and 2 reveal evidence that CDR3 length and J segment frequency are under genetic control, we will specifically explore the hypothesis that MHC haplotype may influence these repertoire parameters. This will be done by performing these analyses in large families of defined HLA type. As part of these family studies, an analysis of T cell receptor inheritance, including V and J segment polymorphisms, will also be performed in order to address the possibility of genetic interactions between the MHC and T cell receptor loci in regulating the peripheral T cell repertoire.